Nitrate Esters as Nitric Oxide Donors:  SS-Nitrates

Abstract

[structure: see text]. The important biological secondary messenger NO can be generated from exogenous nitrovasodilators and NO donors. Nitrate esters are nitrovasodilators and NO mimetics, believed to be biotransformed to NO in vivo. On the basis of a mechanistic hypothesis, nitrates have been synthesized that release NO at significant rates in neutral aqueous solution in the presence only of added thiol. The novel masked beta-mercaptonitrates reported (SS-nitrates), provide information on possible sulfhydryl-dependent biotransformation mechanisms for nitrates in clinical use.

Cognitive Deficits in Rats after Forebrain Cholinergic Depletion are Reversed by a Novel NO Mimetic Nitrate Ester

“…Enzyme activity in hippocampal homogenates increased 16-to 20-fold at the highest concentration of GT1061, whereas in the aorta, the maximal increase in activity was only 2-to 3-fold. In broken cell preparations, with very rare exceptions, nitrates do not activate sGC above basal levels in the absence of certain added thiols Zavorin et al, 2001); GT1061 is not an exception.…”

NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs

“…20) We have proposed a plausible sulfhydryl-dependent mechanism of NO release from our NO-NSAIDs in our earlier paper. 8,23) In light of FDA's recent negative decision on Nicox's naproxcinod (I), 6) we wanted to determine the similarities as well as differences in NO release profiles of naproxcinod (I) and our NO-NSAIDs.…”

“…Organic nitrates containing a sulfur atom at β-position to a nitrate group were originally termed as "SS-nitrates," 20) and they were designed to prove the hypothesized sulfhydryl-dependent mechanism of NO release from organic nitrates such as glyceryl trinitrate (GTN). 21,22) Such 'SS-nitrates' exhibited good stability in neutral aqueous solution but released significant amounts of NO in aqueous medium at biologically relevant pH on addition of sulfhydryl-containing compounds.…”

“…21,22) Such 'SS-nitrates' exhibited good stability in neutral aqueous solution but released significant amounts of NO in aqueous medium at biologically relevant pH on addition of sulfhydryl-containing compounds. 20) By partly adopting this "SS-nitrate" feature into our disulfide-linker containing prodrug strategy, 7) we have designed, synthesized and evaluated NO-NSAID prodrugs that contain a NO-releasing nitrate moiety at β-position to the disulfide group, which is, in turn, covalently bonded through "CH 2 CH 2 " chain to the carboxyl group of parent NSAIDs via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33) as shown in Fig. 2.…”

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

“…The novel nitrate, GT 715, represents a prototype for one such approach [198,199]. GTN and GT715 were shown to exert differential effects on cardiovascular function, with GT715, being a weaker vasodilator with minimal effects on mean arterial pressure in the whole animal compared to GTN [190].…”